Safety and efficacy of once-daily HU6 versus placebo in people with non-alcoholic fatty liver disease and high BMI: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: HU6 is a controlled metabolic accelerator that is metabolised in the liver to the mitochondrial uncoupler 2,4-dinitrophenol and increases substrate utilisation so that fat and other carbon sources are oxidised in the body rather than accumulated. We aimed to assess the safety and efficacy of HU6 compared with placebo in people with non-alcoholic fatty liver disease (NAFLD) and high BMI. METHODS: This randomised, double-blind, placebo-controlled, phase 2a trial was done at a single community site in the USA. Adults (aged 28-65 years) with a BMI of 28-45 kg/m2, a FibroScan controlled attenuation parameter score of more than 270 decibels per metre, and at least 8% liver fat by MRI-proton density fat fraction (MRI-PDFF) were randomly assigned (1:1:1:1) to receive, under fasting conditions, either once-daily HU6 100 mg, HU6 300 mg, HU6 450 mg, or matching placebo by oral administration for 61 days. Randomisation was blocked (groups of four) and stratified by baseline glycated haemoglobin (<5·7% vs ≥5·7%; 39 mmol/mol). All participants and study personnel involved with outcome assessments were masked to treatment assignment. The primary endpoint was the relative change in liver fat content from baseline to day 61, as assessed by MRI-PDFF, and was analysed in the full analysis set (FAS), which comprised all participants who were randomly assigned, received at least one dose of treatment, and had less than 4·5 kg of weight gain or weight loss from the time of screening to day 1 of treatment. The safety population included all participants who were randomly assigned and received at least one dose of study drug. This study was registered at ClinicalTrials.gov, NCT04874233, and is complete. FINDINGS: Between April 28, 2021, and Nov 29, 2021, 506 participants were assessed for eligibility and 80 adults (39 [49%] women and 41 [51%] men) were enrolled and randomly assigned to placebo (n=20), HU6 150 mg (n=20), HU6 300 mg (n=21), or HU6 450 mg (n=19). One participant in the HU6 450 mg group was excluded from the FAS due to weight gain. Relative mean change in liver fat content from baseline to day 61 was -26·8% (SD 17·4) for the HU6 150 mg group, -35·6% (13·8) for the HU6 300 mg group, -33·0% (18·4) for the HU6 450 mg group, and 5·4% (19·8) for the placebo group. Three people treated with HU6 (two treated with 150 mg and one treated with 300 mg) and two people treated with placebo discontinued treatment due to treatment-emergent adverse events (TEAEs). No serious TEAEs were reported. In those treated with HU6, flushing (19 [32%] participants), diarrhoea (15 [25%] participants), and palpitations (seven [12%] participants) were the most frequently reported TEAEs (in the placebo group, two [10%] participants had flushing, none had diarrhoea, and one [5%] had palpitations). There were no deaths. INTERPRETATION: HU6 could be a promising pharmacological agent for treating patients with obesity and NAFLD and its metabolic complications. FUNDING: Rivus Pharmaceuticals.

Rehabilitation Perspectives in Long COVID-19.

Long COVID is a term used to describe the persistence of symptoms in people who have had COVID-19 for an extended period. It affects multiple systems including neurological (fatigue, brain fog, attention issues, memory issues), neuromuscular (sarcopenia, myositis, arthritis and myopathy), cardiovascular (myopericarditis, right ventricular dysfunction, vasculitis and aortic, arterial and venous thrombosis) and respiratory (pulmonary fibrosis, pleurisy, pulmonary embolism and pneumonitis). This results in functional impairments which adversely affect the quality of life of patients. The rehabilitation of persons who have experienced long COVID-19, also known as "long haulers," is a relatively new field of study. We have described potential rehabilitation interventions to improve functional capacity and quality of life in patients with long COVID. These rehabilitation interventions include but are not limited to, endurance, flexibility and strength training, pulmonary rehabilitation, task specific exercises to improve Activities of Daily Living (ADL), psychological rehabilitation, medical rehabilitation, pain management and management of dysphagia.

Beta-Blockers in the Prevention and Treatment of Ischemic Heart Disease: Evidence and Clinical Practice.

Coronary artery disease (CAD) is the most prevalent cardiovascular disease characterized by atherosclerotic plaque buildup that can lead to partial or full obstruction of blood flow in the coronary arteries. Treatment for CAD involves a combination of lifestyle changes, pharmacologic therapy, and modern revascularization procedures. Beta-adrenoceptor antagonists (or beta-blockers) have been widely used for decades as a key therapy for CAD. In this review, prior studies are examined to better understand beta-adrenoceptor antagonist use in patients with acute coronary syndrome, stable coronary heart disease, and in the perioperative setting. The evidence for the benefit of beta-blocker therapy is well established for patients with acute myocardial infarction, but it diminishes as the time from the index cardiac event elapses. The evidence for benefit in the perioperative setting is not strong.

A Systematic Review of Whether the Use of N95 Respirator Masks Decreases the Incidence of Cardiovascular Disease in the General Population.

The usage of masks such as the N95 has increased exponentially worldwide. With the ever-increasing global rates of cardiovascular disease, it is vital that preventative measures are adopted to help tackle this crisis. N95 masks have been promoted as health prevention odysseys in the battle against viruses such as COVID-19. A systematic review was conducted on whether the N95 masks could help improve our cardiovascular health. Our data sources included PubMed, Medline and Scopus. Eleven studies met the eligibility criteria to be included in the review. N95 mask usage led to increased reports of dyspnoea, however, no significant effect was seen on blood pressure. N95 masks also showed improvement in aortic parameters. While encouraging results were yielded, further focussed studies on the use of N95 masks and the effect on various cardiovascular parameters would help strengthen the association.

Effects of aerobic exercise and progressive muscle relaxation on migraine.

OBJECTIVE: To determine the effect of aerobic exercises and progressive muscle relaxation in migraine patients. METHODS: The quasi-experimental study was conducted at the Sheikh Khalifa Bin Zayed Al Nayhan Hospital / Combined Military Hospital, Muzaffarabad, Azad Jammu and Kashmir, from February to July 2017, and comprised migraine patients of either gender aged 20-50 years. They were divided into experimental and control group. Experimental group A received supervised exercises protocol, including aerobic exercise (stationary bicycle) 30min with 10min warm-up and 5min cool-down followed by progressive muscle relaxation for 15min 3 times a week for 6 weeks along with prophylactic medicine. The control group received prophylactic medicines flunarazine 5mg twice daily, inderal 10mg thrice daily and nortriptyline 25mg at night. Patients were assessed using Numeric Pain Rating Scale, Migraine Disability Assessment Scale, Headache Disability Index, Headache Impact test-6 and the Central Sensitisation Inventory at baseline, midline and at the completion of intervention. Data was analysed using SPSS 21. RESULTS: Of the 28 patients, there were 14(50%) in each of the two groups. Overall, there were 24(85.7%) females and 4(14.3%) males with a mean age of 29.7±10 years. There were significant improvements in all parameters in both the groups, but group A had significantly better outcome post-intervention (p<0.05). CONCLUSIONS: Prophylactic medicine, aerobic exercises and progressive muscle relaxation, when used together, were found to be effective means of intervention for migraine.

The Use of Amikacin Liposome Inhalation Suspension (Arikayce) in the Treatment of Refractory Nontuberculous Mycobacterial Lung Disease in Adults.

Nontuberculous mycobacteria (NTM) can cause and perpetuate chronic inflammation and lung infection. Despite having the diagnostic criteria, as defined by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA), clinicians find it challenging to diagnose and treat NTM-induced lung disease. Inhaled antibiotics are suitable for patients with lung infection caused by Pseudomonas aeruginosa and other organisms, but until recently, their utility in NTM-induced infection was not established. The most common NTM pathogens identified are the slow-growing Mycobacterium avium complex (MAC) and the rapid-growing M. abscessus complex (MABSC), both of which include several subspecies. Other less commonly isolated species include M. kansasii, M. simiae, and M. fortuitum. NTM strains are frequently more resistant than what is found in bacterial sputum cultures. Until recently, there was no approved inhaled antibiotic therapy for patients who were culture positive for pulmonary NTM infection. Of late, inhaled amikacin has been under investigation for the treatment of NTM-induced pulmonary infection. The FDA approved Arikayce (amikacin liposome inhalation suspension or ALIS) based on results from the ongoing Phase 3 CONVERT trial. In this study, the use of Arikayce met its primary endpoint of sputum culture conversion by the sixth month of treatment. The addition of Arikayce to guideline-based therapy led to negative sputum cultures for NTM by month 6 in 29% of patients compared to 8.9% of patients treated with guideline-based therapy alone. The effectiveness of Arikayce holds promise. However, due to limited data on Arikayce's safety, it is currently useful only for a specific population, particularly patients with refractory NTM-induced lung disease. Future trials must verify the target group and endorse the clinical benefits of Arikayce.

Effect of Coronary Artery Disease risk SNPs on serum cytokine levels and cytokine imbalance in Premature Coronary Artery Disease.

BACKGROUND: Premature Coronary Artery Disease (PCAD) occurs almost a decade earlier in the South Asian population as compared to the West. Inclusion of genetic information can prove to be a robust measure to improve early risk prediction of PCAD. Aim was to estimate the genotypic distribution and risk allele frequencies of 13 Coronary Artery Disease (CAD) risk Single Nucleotide Polymorphisms in loci identified by the CARDIoGRAMplusC4D consortium namely MIA3 rs17465637; 9p21 rs10757274; CXCL12 rs1746048; APOA5 rs662799; APOB rs1042031; LPA rs3798220; LPA 10455872; MRAS rs9818870; LPL rs328; SORT1 rs646776; PCSK9 rs11591147; APOE rs429358; APOE rs7412 in Pakistani PCAD patients and controls. Moreover, the differential serum cytokine levels (IL-18, IL-10, IL-6, TNF-alpha, IL-18:IL-10 & TNF-alpha:IL-10 ratios) with respect to the genotypic distribution of these selected SNPs were determined. MATERIAL AND METHODS: The case-control study was carried out in National University of Sciences and Technology, Islamabad in collaboration with the Cardiovascular Genetics Institute, University College London, UK. Subjects (n=340) with >70% stenosis in at least a single major coronary artery on angiography were taken as PCAD cases along with 310 angiographically verified controls. ELISA was performed for measuring the concentrations of serum IL18, TNFA, IL6 and IL10. Genotyping was done using TAQMAN and KASPar assays. RESULTS: The risk allele frequencies (RAF) of APOE rs7412, CXCL12 rs1746048, 9p21 rs10757274, MIA3 rs17465637 and SORT1 rs646776 were significantly higher in the PCAD cases as compared to the controls. APOE rs429358 had the greatest influence among the selected GWAS/CARDIoGRAMplusC4D consortium CAD risk SNPs by significantly altering the serum levels of TNF-alpha, IL-10 and TNF-alpha:IL-10 ratio. It was followed by APOE rs7412 and CXCL12 rs1746048 which significantly altered the serum levels of IL-18; TNF-alpha and IL-18; IL-18:IL-10 ratio respectively. The cytokine imbalance denoted by IL-18:IL-10 was significantly higher in the risk allele carriers MIA3 rs17465637 and CXCL12 rs1746048 while TNF-alpha:IL-10 ratio was significantly raised in the risk allele carriers of APOE rs429358; MRAS rs9818870 and LPL rs328. CONCLUSION: The association of the selected SNPs with differential serum cytokine levels especially the cytokine imbalance points towards their potential causal role in the immune inflammatory pathogenic pathway of PCAD.

Compression Stockings and Pressure Ulcers: Case Series of a Neglected Issue.

Pressure ulcers develop in patients who endure long periods of immobilization, often caused by conditions such as musculoskeletal and neurological diseases. Pressure ulcers adversely affect the patient and increase caregiver burden and healthcare costs. Typical sites for these ulcers include the sacrum, trochanters, and heels; they also occur on the nape of the neck, penis, nostrils, helix of the ear, and upper back. Compression stockings are commonly used to prevent and stop the progression of venous disorders, including deep vein thrombosis, but their role in the development of pressure ulcers is not well known. We describe three case reports of pressure ulcer development due to prolonged application of compression stockings. In each case, the nursing staff who were primarily responsible for the prevention of pressure ulcers applied the stockings continuously without any intermittent relief. Moreover, the stockings did not include manufacturer instructions, such as recommended exposure times and applications. We recommend that nursing staff be trained in pressure relief and prevention of pressure ulcers, including rare occurrences, and that manufacturers give detailed guidance regarding the safe use of compression stockings.

Influence of cytokine gene polymorphisms on proinflammatory/anti-inflammatory cytokine imbalance in premature coronary artery disease.

BACKGROUND: Genetic information has the potential to create a more personalised, prompt, early and accurate risk evaluation. The effect of these genetic variants on the serum biomarker levels (phenotype) needs to be studied to assess their potential causal role in the pathogenesis of premature coronary artery disease (PCAD). Objectives were to determine the genotypic distribution of interleukin (IL) 18, tumour necrosis factor-α (TNFA), IL6 and IL10 single nucleotide polymorphisms (SNPs) in Pakistani PCAD cases and disease free controls and to study the effect of these gene polymorphisms on the serum cytokine levels (IL18, TNFA, IL6 and IL10) and cytokine imbalance (IL18:IL10 and TNFA:IL10). MATERIAL AND METHODS: The case-control study was carried out in National University of Sciences and Technology, Islamabad in collaboration with the Cardiovascular Genetics Institute, University College London, UK. Subjects (n=340) with >70% stenosis in at least a single major coronary artery on angiography were taken as PCAD cases along with 310 angiographically verified controls. ELISA was performed for measuring the concentrations of serum IL18, TNFA, IL6 and IL10. Genotyping was done using TAQMAN assay. RESULTS: The risk allele frequencies (RAFs) of rs1800795 (IL6) and rs187238 (IL18) cytokine gene promoter SNPs were significantly higher in the PCAD cases as compared with the controls. Serum IL18 and IL10 levels were significantly greater in the IL18 rs187238 GG genotype patients while serum IL18 and IL6 levels were significantly higher in patients having the IL6 rs1800795 CC genotype. IL18 SNP rs1946519 significantly altered the IL18, TNFA, IL6, IL18/IL10 and TNFA/IL10 ratio levels followed by TNFA SNP rs1800629 which significantly altered the serum levels of IL18, IL18:IL-0 and TNFA:IL10 ratios. CONCLUSIONS: The association of the selected SNPs with differential serum cytokine levels especially the cytokine imbalance points towards their potential causal role in the immune inflammatory pathogenic pathway of PCAD.

Role of Cytokine Gene Score in Risk Prediction of Premature Coronary Artery Disease.

AIMS: Pro- and anti-inflammatory cytokines play a significant role in early atherosclerosis. Linkage disequilibrium patterns differ between ethnic groups pointing toward the need to develop population-specific gene risk scores. Our objective was to investigate the role of a cytokine gene score in the risk prediction of premature coronary artery disease (PCAD). METHODS: A case-control study was performed at the National University of Sciences and Technology (NUST) in collaboration with the Cardiovascular Genetics Institute, University College London, United Kingdom. Three hundred forty subjects with >70% stenosis in at least one coronary vessel on angiography were labeled as PCAD cases and compared with 310 angio-negative controls. Genotyping of the rs187238 (interleukin [IL]-18), rs1800795 (IL-6), rs1800629 (tumor necrosis factor [TNF]-alpha), rs1800871 (IL-10), and rs1946519 (IL-18) SNPs was performed using KASPar and TaqMan assays. RESULTS: The odds ratio for cytokine gene score was significantly higher for PCAD (p = 0.025) when adjusted for age, sex, and ethnicity. There was a highly significant difference in gene risk allele frequency between Pakistanis and Caucasians (Northwick Park Heart Study II [NPHSII]) for rs187238 (IL-18), rs1800795 (IL-6), rs1800629 (TNF-alpha), and rs1800871 (IL-10) (p < 0.01). CONCLUSIONS: A cytokine gene score has significant discriminatory ability and potential in the risk prediction of PCAD. Cytokine gene risk allele frequencies differ significantly between Pakistanis and Caucasians supporting the need to develop population-specific gene scores.

The efficacy, safety and ethics of the use of testosterone-suppressing agents in the management of sex offending.

PURPOSE OF REVIEW: The use of endocrine medications to reduce sexual offending recidivism is established and may involve clinicians from diverse specialities. The present review aims to outline relevant background information and note a Medical Ethics framework upon which to facilitate decision-making. RECENT FINDINGS: There have been several systematic reviews in recent years. A number of problems with research in the area of the medical treatment of sex offenders have been highlighted. There remains scope for improvement in the research to answer a number of relevant clinical issues. Nonetheless, some very useful indicators of relevance to clinical practice have emerged. SUMMARY: The use of medication to manage the risk of sex offending in males is appropriate under the right circumstances. These include, for example, hypersexuality with sexual deviance and psychological-treatment interfering sexual preoccupation.

Pharmacological interventions for those who have sexually offended or are at risk of offending.

BACKGROUND: Sexual offending is a serious social problem, a public health issue, and a major challenge for social policy. Victim surveys indicate high incidence and prevalence levels and it is accepted that there is a high proportion of hidden sexual victimisation. Surveys report high levels of psychiatric morbidity in survivors of sexual offences.Biological treatments of sex offenders include antilibidinal medication, comprising hormonal drugs that have a testosterone-suppressing effect, and non-hormonal drugs that affect libido through other mechanisms. The three main classes of testosterone-suppressing drugs in current use are progestogens, antiandrogens, and gonadotropin-releasing hormone (GnRH) analogues. Medications that affect libido through other means include antipsychotics and serotonergic antidepressants (SSRIs). OBJECTIVES: To evaluate the effects of pharmacological interventions on target sexual behaviour for people who have been convicted or are at risk of sexual offending. SEARCH METHODS: We searched CENTRAL (2014, Issue 7), Ovid MEDLINE, EMBASE, and 15 other databases in July 2014. We also searched two trials registers and requested details of unidentified, unpublished, or ongoing studies from investigators and other experts. SELECTION CRITERIA: Prospective controlled trials of antilibidinal medications taken by individuals for the purpose of preventing sexual offences, where the comparator group received a placebo, no treatment, or 'standard care', including psychological treatment. DATA COLLECTION AND ANALYSIS: Pairs of authors, working independently, selected studies, extracted data, and assessed the risk of bias of included studies. We contacted study authors for additional information, including details of methods and outcome data. MAIN RESULTS: We included seven studies with a total of 138 participants, with data available for 123. Sample sizes ranged from 9 to 37. Judgements for categories of risk of bias varied: concerns were greatest regarding allocation concealment, blinding of outcome assessors, and incomplete outcome data (dropout rates in the five community-based studies ranged from 3% to 54% and results were usually analysed on a per protocol basis).Participant characteristics in the seven studies were heterogeneous, but the vast majority had convictions for sexual offences, ranging from exhibitionism to rape and child molestation.Six studies examined the effectiveness of three testosterone-suppressing drugs: cyproterone acetate (CPA), ethinyl oestradiol (EO), and medroxyprogesterone acetate (MPA); a seventh evaluated two antipsychotics (benperidol and chlorpromazine). Five studies were placebo-controlled; in two, MPA was administered as an adjunctive treatment to a psychological therapy (assertiveness training or imaginal desensitisation). Meta-analysis was not possible due to heterogeneity of interventions, comparators, study designs, and other issues. The quality of the evidence overall was poor. In addition to methodological issues, much evidence was indirect. PRIMARY OUTCOME: recividism. Two studies reported recidivism rates formally. One trial of intramuscular MPA plus imaginal desensitisation (ID) found no reports of recividism at two-year follow-up for the intervention group (n = 10 versus one relapse within the group treated by ID alone). A three-armed trial of oral MPA, alone or in combination with psychological treatment, reported a 20% rate of recidivism amongst those in the combined treatment arm (n = 15) and 50% of those in the psychological treatment only group (n = 12). Notably, all those in the 'oral MPA only' arm of this study (n = 5) dropped out immediately, despite treatment being court mandated.Two studies did not report recidivism rates as they both took place in one secure psychiatric facility from which no participant was discharged during the study, whilst another three studies did not appear directly to measure recividism but rather abnormal sexual activity alone. SECONDARY OUTCOMES: The included studies report a variety of secondary outcomes. Results suggest that the frequency of self reported deviant sexual fantasies may be reduced by testosterone-suppressing drugs, but not the deviancy itself (three studies). Where measured, hormonal levels, particularly levels of testosterone, tended to correlate with measures of sexual activity and with anxiety (two studies). One study measured anxiety formally; one study measured anger or aggression. Adverse events: Six studies provided information on adverse events. No study tested the effects of testosterone-suppressing drugs beyond six to eight months and the cross-over design of some studies may obscure matters (given the 'rebound effect' of some hormonal treatments). Considerable weight gain was reported in two trials of oral MPA and CPA. Side effects of intramuscular MPA led to discontinuation in some participants after three to five injections (the nature of these side effects was not described). Notable increases in depression and excess salivation were reported in one trial of oral MPA. The most severe side effects (extra-pyramidal movement disorders and drowsiness) were reported in a trial of antipsychotic medication for the 12 participants in the study. No deaths or suicide attempts were reported in any study. The latter is important given the association between antilibidinal hormonal medication and mood changes. AUTHORS' CONCLUSIONS: We found only seven small trials (all published more than 20 years ago) that examined the effects of a limited number of drugs. Investigators reported issues around acceptance and adherence to treatment. We found no studies of the newer drugs currently in use, particularly SSRIs or GnRH analogues. Although there were some encouraging findings in this review, their limitations do not allow firm conclusions to be drawn regarding pharmacological intervention as an effective intervention for reducing sexual offending.The tolerability, even of the testosterone-suppressing drugs, was uncertain given that all studies were small (and therefore underpowered to assess adverse effects) and of limited duration, which is not consistent with current routine clinical practice. Further research is required before it is demonstrated that their administration reduces sexual recidivism and that tolerability is maintained.It is a concern that, despite treatment being mandated in many jurisdictions, evidence for the effectiveness of pharmacological interventions is so sparse and that no RCTs appear to have been published in two decades. New studies are therefore needed and should include trials with larger sample sizes, of longer duration, evaluating newer medications, and with results stratified according to category of sexual offenders. It is important that data are collected on the characteristics of those who refuse and those who drop out, as well as those who complete treatment.

Personality disorder traits and self-reported target problems in a treatment-seeking sample.

BACKGROUND: Assessments of personality disorder (PD) by clinicians or researchers are not always congruent with the problems that clients view as most salient. This can result in disagreement over areas for change, leading to dissatisfaction and the risk of treatment attrition. METHOD: The sample comprised 141 treatment-seeking adults with PD. Each described the five things they most wanted to change about themselves. These target problems were compared with PD diagnoses obtained from the International Personality Disorder Examination. RESULTS: The congruence between the clients' target problems and PD traits identified by the professionals was generally weak. Disagreement arose where a client's target problem was not a PD trait and, less frequently, where the client and the professional agreed on the presence of a trait but not on its importance. Surprisingly, doubting the trustworthiness of others was the most commonly reported target problem in this treatment-seeking sample even though many such participants did not qualify for that particular paranoid trait. CONCLUSION: Personality disorder diagnoses were generally poor indicators of the problems these clients cited as most important. This lack of correspondence may explain some of the lack of effectiveness of interventions for PD. KEY PRACTITIONER MESSAGE: The problem that a client with personality disorder (PD) views as most important may only be weakly identified in a formal diagnostic assessment. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PD traits are insufficient to describe fully the things clients most want to change about themselves. Many clients with PD consider difficulty trusting others to be their most important problem, despite not qualifying for that particular paranoid trait. Risk of disagreement between the clinician and the client might be reduced if both parties can engage in a discussion about the results of any formal diagnostic assessment.

Psychological interventions for adults who have sexually offended or are at risk of offending.

BACKGROUND: Sexual offending is a legal construct that overlaps, but is not entirely congruent with, clinical constructs of disorders of sexual preference. Sexual offending is both a social and a public health issue. Victim surveys illustrate high incidence and prevalence levels, and it is commonly accepted that there is considerable hidden sexual victimisation. There are significant levels of psychiatric morbidity in survivors of sexual offences.Psychological interventions are generally based on behavioural or psychodynamic theories.Behavioural interventions fall into two main groups: those based on traditional classical conditioning and/or operant learning theory and those based on cognitive behavioural approaches. Approaches may overlap. Interventions associated with traditional classical and operant learning theory are referred to as behaviour modification or behaviour therapy, and focus explicitly on changing behaviour by administering a stimulus and measuring its effect on overt behaviour. Within sex offender treatment, examples include aversion therapy, covert sensitisation or olfactory conditioning. Cognitive behavioural therapies are intended to change internal processes - thoughts, beliefs, emotions, physiological arousal - alongside changing overt behaviour, such as social skills or coping behaviours. They may involve establishing links between offenders' thoughts, feelings and actions about offending behaviour; correction of offenders' misperceptions, irrational beliefs and reasoning biases associated with their offending; teaching offenders to monitor their own thoughts, feelings and behaviours associated with offending; and promoting alternative ways of coping with deviant sexual thoughts and desires.Psychodynamic interventions share a common root in psychoanalytic theory. This posits that sexual offending arises through an imbalance of the three components of mind: the id, the ego and the superego, with sexual offenders having temperamental imbalance of a powerful id (increased sexual impulses and libido) and a weak superego (a low level of moral probation), which are also impacted by early environment.This updates a previous Cochrane review but is based on a new protocol. OBJECTIVES: To assess the effects of psychological interventions on those who have sexually offended or are at risk of offending. SEARCH METHODS: In September 2010 we searched: CENTRAL, MEDLINE, Allied and Complementary Medicine (AMED), Applied Social Sciences Index and Abstracts (ASSIA), Biosis Previews, CINAHL, COPAC, Dissertation Abstracts, EMBASE, International Bibliography of the Social Sciences (IBSS), ISI Proceedings, Science Citation Index Expanded (SCI), Social Sciences Citation Index (SSCI), National Criminal Justice Reference Service Abstracts Database, PsycINFO, OpenSIGLE, Social Care Online, Sociological Abstracts, UK Clinical Research Network Portfolio Database and ZETOC. We contacted numerous experts in the field. SELECTION CRITERIA: Randomised trials comparing psychological intervention with standard care or another psychological therapy given to adults treated in institutional or community settings for sexual behaviours that have resulted in conviction or caution for sexual offences, or who are seeking treatment voluntarily for behaviours classified as illegal. DATA COLLECTION AND ANALYSIS: At least two authors, working independently, selected studies, extracted data and assessed the studies' risk of bias. We contacted study authors for additional information including details of methods and outcome data. MAIN RESULTS: We included ten studies involving data from 944 adults, all male.Five trials involved primarily cognitive behavioural interventions (CBT) (n = 664). Of these, four compared CBT with no treatment or wait list control, and one compared CBT with standard care. Only one study collected data on the primary outcome. The largest study (n = 484) involved the most complex intervention versus no treatment. Long-term outcome data are reported for groups in which the mean years 'at risk' in the community are similar (8.3 years for treatment (n = 259) compared to 8.4 in the control group (n = 225)). There was no difference between these groups in terms of the risk of reoffending as measured by reconviction for sexual offences (risk ratio (RR) 1.10; 95% CI 0.78 to 1.56).Four trials (n = 70) compared one behavioural programme with an alternative behavioural programme or with wait list control. No meta-analysis was possible for this comparison. For two studies (both cross-over, n = 29) no disaggregated data were available. The remaining two behavioural studies compared imaginal desensitisation with either covert sensitisation or as part of adjunctive drug therapy (n = 20 and 21, respectively). In these two studies, results for the primary outcome (being 'charged with anomalous behaviour') were encouraging, with only one new charge for the treated groups over one year in the former study, and in the latter study, only one new charge (in the drug-only group) over two years.One study compared psychodynamic intervention with probation. Results for this study (n = 231) indicate a slight trend in favour of the control group (probation) over the intervention (group therapy) in terms of sexual offending as measured by rearrest (RR 1.87; 95% CI 0.78 to 4.47) at 10-year follow-up.Data for adverse events, 'sexually anomalous urges' and for secondary outcomes thought to be 'dynamic' risk factors for reoffending, including anger and cognitive distortions, were limited. AUTHORS' CONCLUSIONS: The inescapable conclusion of this review is the need for further randomised controlled trials. While we recognise that randomisation is considered by some to be unethical or politically unacceptable (both of which are based on the faulty premise that the experimental treatment is superior to the control - this being the point of the trial to begin with), without such evidence, the area will fail to progress. Not only could this result in the continued use of ineffective (and potentially harmful) interventions, but it also means that society is lured into a false sense of security in the belief that once the individual has been treated, their risk of reoffending is reduced. Current available evidence does not support this belief. Future trials should concentrate on minimising risk of bias, maximising quality of reporting and including follow-up for a minimum of five years 'at risk' in the community.

RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice.

Mitochondrial function declines with age in postmitotic tissues such as brain, heart and skeletal muscle. Despite weekly exercise, aged mice showed substantial losses of mtDNA gene copy numbers and reductions in mtDNA gene transcription and mitobiogenesis signaling in brain and heart. We treated these mice with weekly intravenous injections of recombinant human mitochondrial transcription factor A (rhTFAM). RhTFAM treatment for one month increased mitochondrial respiration in brain, heart and muscle, POLMRT expression and mtDNA gene transcription in brain, and PGC-1 alpha mitobiogenesis signaling in heart. RhTFAM treatment reduced oxidative stress damage to brain proteins, improved memory in Morris water maze performance and increased brain protein levels of BDNF and synapsin. Microarray analysis showed co-expression of multiple Gene Ontology families in rhTFAM-treated aged brains compared to young brains. RhTFAM treatment reverses age-related memory impairments associated with loss of mitochondrial energy production in brain, increases levels of memory-related brain proteins and improves mitochondrial respiration in brain and peripheral tissues.

Pharmacological interventions for those who have sexually offended or are at risk of offending.

This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the effects of pharmacological interventions on target sexual behaviour for people who have been convicted or at risk of sexual offending.

National trends and practices in breast MRI.

OBJECTIVE: The objective of our study was to report on the current practices of radiologists involved in the performance and interpretation of breast MRI in the United States. MATERIALS AND METHODS: We invited the 1,696 active physician members of the Society of Breast Imaging to participate in a survey addressing whether and how they performed and interpreted breast MRI. Respondents were asked to select one member of their practice to complete the survey. A total of 754 surveys were completed. Every respondent did not reply to every question. RESULTS: Contrast-enhanced breast MRI was offered at 557 of 754 (73.8%) practices. Of these, 346 of 553 (62.6%) performed at least five breast MRI examinations per week, and only 56 of 553 (10.1%) performed > 20 per week. Radiologists qualified under the Mammography Quality Standards Act supervised the performance of and interpreted breast MRI in the majority of facilities. Of 552 respondents, breast MRI was interpreted as soft copy with computer-aided detection (CAD) in 280 practices (50.7%), as soft copy without CAD in 261 (47.3%), and as hard copy in 11 (2.0%). Of 551 respondents, 256 (46.5%) never and 207 (37.6%) rarely interpreted breast MRI without correlating mammography or sonography findings. The majority of respondents never (269/561, 48.0%) or rarely (165/561, 29.4%) interpreted breast MRI performed at an outside facility. Screening breast MRI was offered at 359 of 561 (64.0%) practices. Of the practices performing contrast-enhanced examinations, 173 of 557 (31.1%) did not perform MRI-guided interventional procedures. CONCLUSION: Contrast-enhanced breast MRI is now widely used in the United States. The information gained from this survey should provide reasonable approaches for the development of professional practice guidelines.